Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
  • B01J20/282—Porous sorbents
  • B01J20/285—Porous sorbents based on polymers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
  • B01J20/26—Synthetic macromolecular compounds
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
  • B01J20/26—Synthetic macromolecular compounds
  • B01J20/261—Synthetic macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
  • B01J20/26—Synthetic macromolecular compounds
  • B01J20/268—Polymers created by use of a template, e.g. molecularly imprinted polymers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/305—Addition of material, later completely removed, e.g. as result of heat treatment, leaching or washing, e.g. for forming pores
  • B01J20/3057—Use of a templating or imprinting material ; filling pores of a substrate or matrix followed by the removal of the substrate or matrix
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F285/00—Macromolecular compounds obtained by polymerising monomers on to preformed graft polymers
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F291/00—Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
  • B01D15/08—Selective adsorption, e.g. chromatography
  • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
  • B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
  • B01D15/3852—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36 using imprinted phases or molecular recognition; using imprinted phases
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2220/00—Aspects relating to sorbent materials
  • B01J2220/50—Aspects relating to the use of sorbent or filter aid materials
  • B01J2220/54—Sorbents specially adapted for analytical or investigative chromatography

Definitions

• the present invention relates to a molecularly imprinted polymer, to a method for preparing said molecularly imprinted polymer, and to the use of said molecu- larly imprinted polymer.
• MIPs Molecularly imprinted polymers
• the technique shows promise m chiral separations of for example ammo acid derivatives, peptides, phosphonates, ammoalcohols and beta-blocking compounds, affinity chromatography of nucleotides and the DNA-bases as well as substitute for antibodies m immunoassays for commercial drugs.
• MI Molecular imprinting
• This can be through an affinity chromatographic procedure where pH, ion strength or solvent gradients can be used in order to control the strength of interaction with the stationary phase.
• the separation can target enantiomers or diastereomers m a mixture of enantiomers or diastereomers of one or many compounds.
• Analytical applications can m addition to the above mentioned separa- tions be: competetitive binding assays, chemical sensors or selective sample enrichments.
• the materials can be synthesized m any standard equipped laboratory m a relatively short time and some of the MIPs exhibit binding affinities and selectivities m the order of those exhibited by antibodies towards their antigens.
• Most MIPs are synthesized by free radical polymerisation of functional monounsaturated (vinyhc, acrylic, methacrylic) monomers and an excess of cross-linking di- or triunsatu- rated (vmylic, acrylic, methacrylic) monomers resulting m porous organic network materials.
• These polyme ⁇ sa- tions have the advantage of being relatively robust allowing polymers to be prepared m high yield using different solvents (aqueous or organic) and at different temperatures (4) . This is necessary in view of the varying solubilities of the template molecules.
• the template (L-PA) , the functional mono- mer (MAA) and the cross-linking monomer (EDMA) are dissolved in a poorly hydrogen bonding solvent (diluent) of low to medium polarity.
• the free radical polymerisation is then initiated with an azo initiator, commonly azo- N, N' -bis-isobutyronitrile (AIBN) either by photochemical homolysis below room temperature (6 , 7) or thermochemi- cally at 60°C or higher (5) .
• Lower thermochemical initiation temperatures down to 40°C or 30°C may be obtained using azo-N, N' -bis-divaleronitrile (ABDV) and V70 resp. instead of AIBN as initiator (see) .
• the resultant polymer is crushed by mortar and pestle or in a ball mill, extracted by a Soxhlet apparatus, and sieved to a particle size suitable for chromatographic (25-38 ⁇ m) or batch (150-250 ⁇ m) applications.
• the polymers are then evaluated as stationary phases in chromatography by comparing the retention time or capacity factor (k' ) (9) of the template with that of structurally related analogs.
• MI -materials that can be prepared m high yield m the form of regularly shaped particles with low size dispersity and a controlled porosity. These are expected to be superior in terms of mass transfer characteristics and sample load capacity compared to the materials obtained from the monolithic approach.
• Such MIPs have been previously prepared through sus- pens ⁇ on(10, 11)- polymerisation techniques, dispersion polymerisation (12) or precipitation polymerisation (13) . This resulted in spherical particles of a narrow size distribution.
• These procedures have the limitation of being very sensitive to small changes m the manufacturing conditions and the type of solvents and polymerisation conditions that can be applied. Thus the procedures need careful optimization for each new template target which significantly reduces the usefulness of this route. Moreover conditions leading to low dispersity spherical particles may not be compatible with conditions leading to high selectivity and affinity for the template target.
• An alternative to this procedure is the coating of preformed support materials.
• MIPs have been prepared as grafted coatings on oxide supports (14, 16) on organic polymer supports (15) and on the walls of fused silica capillaries (17-19) .
• the former technique allows the use of the wide variety of oxide support materials available with different sizes and porosities.
• Grafting techniques to prepare organic polymer coatings are expected to be generally applicable to molecular imprinting since the structure of the underlying support is already fixed. Thus compared to the large number of factors influencing the end result m suspension or precipitation type polymerisations a smaller number of factors is likely to influence the end result m the preparation of the imprinted coatings. This will make the grafted coatings techniques less sensitive to changes m conditions offering a more robust method.
• These types of coating tech- niqes are furthermore applicable to modify surfaces of monolithic type supports or microchips prepared by lithographic techniques.
• the oxide based materials are rigid porous supports with a limited inner pore volume.
• An alternative support that could potentially carry more grafted imprinted polymer per unit weight and thus allow a higher density of imprinted sites would be to make use of swellable organic resins.
• Merrifield resins containing grafted initiator or monomer could be used.
• Sofar most imprinted coatings have been prepared by grafting polymers to the various surfaces. Thus the surface contains prior to polymerisation polymerizable double bonds that can add to the growing polymer chains m solution linking them to the surface.
• the problem of confining polymer chain growth to the support surface and supress it in solution can be solved by attaching the radical initiator so that the radical formed upon bond homolysis remains bound to the surface.
• the radical formed that is not attached to the surface should undergo rapid reaction to give an unreactive species. It should be possible to prepare the grafted coatings using monomers such as those based on styren/divmylbenzene, methacrylates, acrylates, acrylamides and m the presence of one or more template molecules.
• the present invention relates to a molecularly imprinted polymer obtainable by polymerising a composition comprising at least one monomer, and a template, on a support m a polymerisation medium with a free radical initiator, whereafter the template is removed from the molecularly imprinted polymer obtained, said polymerisation being confined to the surface of the support.
• the invention further relates to a method for preparing a molecularly imprinted polymer which comprises polymerising a composition comprising at least one monomer, and a template, on a support in a polymerisation me- dium with a free radical initiator, whereafter the template is removed from the molecularly imprinted polymer obtained, said polymerisation being confined to the surface of the support .
• the invention relates to the use of a molecularly imprinted polymer as defined above in chromatography, for separations, in chemical sensors, m molecular recognition as stationary phase m capillaries, m selective sample enrichment or m catalysis.
• Fig. 1 illustrates molecular imprinting with L- phenylalamne anilide (L-PA) .
• Fig. 2 illustrates the procedure of confining initiator radicals to the surface of a support
• Fig. 3 illustrates a method for preparing imprinted composite particles.
• Fig. 4A illustrates the use of a presynthesized azo- silane initiator where both ends may be attached to the surface of a support .
• Fig. 4B illustrates an initiator that may be pread- sorbed on a support surface and that is insoluble m the monomer containing solution.
• Fig. 4C illustrates the use of microwaves to selectively heat the particle surface.
• Fig. 4D illustrates the use of miferters such as dithiocarbamate coupled onto the surface.
• the invention refers to a material that consists m a support (porous or nonporous material or planar surface) coated with a polymer layer, a method for its fabrication and use of said material m for instance chroma- tography, for separations, m chemical sensors, m selective sample enrichment, m molecular recognition as stationary phase in capillaries or m catalysis.
• the material is prepared by grafting a polymer layer on the surface of a preformed organic or inorganic support material or surface. The grafting can be combined with the technique of molecular imprinting.
• the polymerisation is confined to the surface of the support by confining the free radical initiator to the support.
• the free radical initiator is bound (covalently or non-covalently such as e.g. by hydrogen bonds) to the surface of the support.
• the free radical initiator is adsorbed to the surface of the support, preferably by dissolving it m a solvent for the free radical initiator, applying the solution to the support, and removing the solvent, said free radical initiator being insoluble m the polymerisation medium or remaining attached to the support surface by adsorptive forces.
• the polymerisation is confined to the surface of the support by subjecting the composition, the support and the free radical initiator to microwave irradiation which selectively heats the support and thereby initiates a polyme ⁇ - sation reaction at the surface of the support.
• the polymerisation is repeated at least once with a different composition to obtain at least one further layer of molecularly imprinted polymer.
• the support used in the present invention is preferably selected from the group consisting of porous and non-porous, planar and non-planar inorganic and organic supports.
• oxides such as alumina and silica
• organic resins in the form of particles such as spheres, or sheets .
• the template used in the present invention may be any molecule or ion and is preferably selected from the group consisting of organic or inorganic molecule entities, ions, antibodies, antigens, amino acids, peptides, proteins, nucleotides, DNA-bases, carbohydrates, drugs, pesticides, and derivatives thereof, etc.
• polymerisation medium as used her- ein means a liquid medium in which the polymerisation is carried out.
• the polymerisation medium may e.g. be a solvent in which the monomers are soluble. It may also be a monomer acting as a solvent for the other components of the polymerisable composition.
• the support surface is prepared as follows. A free radical initiator is bound to the surface either covalently or noncovalently so that the free radicals generated upon initiation remain confined to the surface or vicinity of the surface. The absence of polymer propaga- tion in solution will lead to a higher accessibility of the monomers at the surface. Furthermore this method will allow the tuning of the thickness of the polymer layer.
• peroxy initiators may be used although better re- suits are obtained using the grafted azoinitiator followed by photochemical initiation. High yields of grafted polymer are obtained using silica reacted with toluene- 2 , 4 -diisocyanate (TDI) followed by reaction with ACPA.
• TDI toluene- 2 , 4 -diisocyanate
• Epoxy and chloromethyl modified supports A typical example is as follows. Into a flask, 3 g of epoxy modi- fied particles 50 mL of DMSO, 0.5 g of ACPA and picolme were charged. The reaction mixture was stirred for 5 h at 50°C. After the reaction the particles were washed with methanol and dried.
• Ammo modified supports A typical example is as follows. Into a flask, 3 g of epoxy modified particles 50 mL of DMF, 0.5 g of ACPA and dicyclohexyldicarbodi- lmide (DCCI) and base were charged. The reaction mixture was stirred for 5 h. After the reaction the particles were washed with methanol and dried. The above procedure does not confine all initiator radicals to the surface since the initiator is bound at only one position. This invention describes three alternative procedures to confine the polymerisation to the surface . 1 The use of a presynthesized azosilane (Fig. 4A) . This will more likely lead to a two point attachment of the initiator to the surface.
• Example 2 Synthesis of azosilane for two point coupling of an azo- initiator to a surface or support
• the azosilane was synthesized by mixing 0.5 mole glycidoxypropylt ⁇ methoxysilane (GPS) and 0.25 mole ACPA m 200 mL isopropanol and catalytic amounts of picolme. The reaction was allowed to continue at room temperature and the product isolated by evaporation to dryness followed by purification by column chromatography giving the product m 60 % yield.
• a polar water soluble initiator as for instance an azo-bis-amidine, (24) can be adsorbed to the surface from aqueous solvent, the surface dried and then the polymerisation initiated as described above (Fig. 4B) .
• the free radicals generated from the initiator will stay associated to the surface due to their insolubility m the monomer mixture.
• amidmeazomitiator such as 2 , 2 ' -azobis (N,N' - dimethyleneisobutyramidme) or 2 , 2 ' -azobis (2-amidmo- propane) is dissolved m methanol/water and support par- tides such as silica are added. After several hours of equilibration the solvent is removed by filtration and the particles dried under vacuum.
• Particles are added to a solution of monomers and initiator m a suitable solvent.
• the polymerisation is initiated by microwave irradiation at a wavelength caus- mg local heating of the particles only. .
• miferters such as dithiocarbamate coupled onto the surface (Fig. 4D).(25) (The term “miferter” is an abbreviation for "initiator + transfer agent + terminator” ) .
• Particles or a surface containing bound dithiocarba- mate groups are/is added to a mixture of monomers (concentration about 5 moles/litre) , template and solvent under nitrogen.
• the polymerisation was initiated by irradiation with an ultrahigh pressure mercury UV lamp and allowed to proceed for a certain time. Then the unreacted monomers and template were washed away. The obtained particles or surface can then be immersed in another solution containing another monomer and the procedure repeated. This allows the manufacturing of layered surfaces containing one or more imprinted layers using possibly different templates and layers of different polarity or other functional properties.
• Example 8 Endcappmg of unreacted silanol groups
• the polymerisation can be carried out m a stirred suspension of the particles the monomer mixture since growth only takes place on the surface (see Fig. 3) .
• the initiator modified particles are added to a monomer containing solution and solvent and possibly a template and the suspension stirred.
• the polymerisation is then carried out photochemically or thermally.
• the particles can be based on any inorganic or organic sup- port material and the template on any molecule or ion dissolved in the monomer mixture solution.
• the grafting can also occur on other surfaces such as those generated by lithographic processes or on the walls of capillaries or fibres.
• the thickness of the polymer layer is tunable by varying the time of reaction.
• the resulting particles exhibit high selectivity and affinity for the template, terbutylazine.

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